Traditional healer support to improve HIV viral suppression in rural Uganda (Omuyambi): study protocol for a cluster randomized hybrid effectiveness-implementation trial.

BACKGROUND: Rural African people living with HIV face significant challenges in entering and remaining in HIV care. In rural Uganda, for example, there is a threefold higher prevalence of HIV compared to the national average and lower engagement throughout the HIV continuum of care. There is an urgent need for appropriate interventions to improve entry and retention in HIV care for rural Ugandans with HIV. Though many adults living with HIV in rural areas prioritize seeking care services from traditional healers over formal clinical services, healers have not been integrated into HIV care programs. The Omuyambi trial is investigating the effectiveness of psychosocial support delivered by traditional healers as an adjunct to standard HIV care versus standard clinic-based HIV care alone. Additionally, we are evaluating the implementation process and outcomes, following the Consolidated Framework for Implementation Research. METHODS: This cluster randomized hybrid type 1 effectiveness-implementation trial will be conducted among 44 traditional healers in two districts of southwestern Uganda. Healers were randomized 1:1 into study arms, where healers in the intervention arm will provide 12 months of psychosocial support to adults with unsuppressed HIV viral loads receiving care at their practices. A total of 650 adults with unsuppressed HIV viral loads will be recruited from healer clusters in the Mbarara and Rwampara districts. The primary study outcome is HIV viral load measured at 12 months after enrollment, which will be analyzed by intention-to-treat. Secondary clinical outcome measures include (re)initiation of HIV care, antiretroviral therapy adherence, and retention in care. The implementation outcomes of adoption, fidelity, appropriateness, and acceptability will be evaluated through key informant interviews and structured surveys at baseline, 3, 9, 12, and 24 months. Sustainability will be measured through HIV viral load measurements at 24 months following enrollment. DISCUSSION: The Omuyambi trial is evaluating an approach that could improve HIV outcomes by incorporating previously overlooked community lay supporters into the HIV cascade of care. These findings could provide effectiveness and implementation evidence to guide the development of policies and programs aimed at improving HIV outcomes in rural Uganda and other countries where healers play an essential role in community health. TRIAL REGISTRATION: ClinicalTrials.gov NCT05943548. Registered on July 5, 2023. The current protocol version is 4.0 (September 29, 2023).

Effect of decentralising childhood tuberculosis diagnosis to primary health centre versus district hospital levels on disease detection in children from six high tuberculosis incidence countries: an operational research, pre-post intervention study.

Background: Childhood tuberculosis (TB) remains underdiagnosed largely because of limited awareness and poor access to all or any of specimen collection, molecular testing, clinical evaluation, and chest radiography at low levels of care. Decentralising childhood TB diagnostics to district hospitals (DH) and primary health centres (PHC) could improve case detection. Methods: We conducted an operational research study using a pre-post intervention cross-sectional study design in 12 DHs and 47 PHCs of 12 districts across Cambodia, Cameroon, Côte d'Ivoire, Mozambique, Sierra Leone and Uganda. The intervention included 1) a comprehensive diagnosis package at patient-level with tuberculosis screening for all sick children and young adolescents <15 years, and clinical evaluation, Xpert Ultra-testing on respiratory and stool samples, and chest radiography for children with presumptive TB, and 2) two decentralisation approaches (PHC-focused or DH-focused) to which districts were randomly allocated at country level. We collected aggregated and individual data. We compared the proportion of tuberculosis detection in children and young adolescents <15 years pre-intervention (01 August 2018-30 November 2019) versus during intervention (07 March 2020-30 September 2021), overall and by decentralisation approach. This study is registered with ClinicalTrials.gov, NCT04038632. Findings: TB was diagnosed in 217/255,512 (0.08%) children and young adolescent <15 years attending care pre-intervention versus 411/179,581 (0.23%) during intervention, (OR: 3.59 [95% CI 1.99-6.46], p-value<0.0001; p-value = 0.055 after correcting for over-dispersion). In DH-focused districts, TB diagnosis was 80/122,570 (0.07%) versus 302/86,186 (0.35%) (OR: 4.07 [1.86-8.90]; p-value = 0.0005; p-value = 0.12 after correcting for over-dispersion); and 137/132,942 (0.10%) versus 109/93,395 (0.11%) in PHC-focused districts, respectively (OR: 2.92 [1.25-6.81; p-value = 0.013; p-value = 0.26 after correcting for over-dispersion). Interpretation: Decentralising and strengthening childhood TB diagnosis at lower levels of care increases tuberculosis case detection but the difference was not statistically significant. Funding source: Unitaid, Grant number 2017-15-UBx-TB-SPEED.

Population Pharmacokinetics of Pediatric Lopinavir/Ritonavir Oral Pellets in Children Living with HIV in Africa.

Antiretroviral therapy for children living with HIV (CLHIV) under 3 years of age commonly includes lopinavir/ritonavir (LPV/r). However, the original liquid LPV/r formulation has taste and cold storage difficulties. To address these challenges, LPV/r oral pellets have been developed. These pellets can be mixed with milk or food for administration and do not require refrigeration. We developed the population pharmacokinetic (PK) model and assessed drug exposure of LPV/r oral pellets administered twice daily to CLHIV per World Health Organization (WHO) weight bands. The PK analysis included Kenyan and Ugandan children participating in the LIVING studies (NCT02346487) receiving LPV/r pellets (40/10 mg) and ABC/3TC (60/30 mg) dispersible tablets. Population PK models were developed for lopinavir (LPV) and ritonavir (RTV) to evaluate the impact of RTV on the oral clearance (CL/F) of LPV. The data obtained from the study were analyzed using nonlinear mixed-effects modeling approach. Data from 514 children, comprising a total of 2,998 plasma concentrations of LPV/r were included in the analysis. The LPV and RTV concentrations were accurately represented by a one-compartment model with first-order absorption (incorporating a lag-time) and elimination. Body weight influenced LPV and RTV PK parameters. The impact of RTV concentrations on the CL/F of LPV was characterized using a maximum effect model. Simulation-predicted target LPV exposures were achieved in children with this pellet formulation across the WHO weight bands. The LPV/r pellets dosed in accordance with WHO weight bands provide adequate LPV exposures in Kenyan and Ugandan children weighing 3.0 to 24.9 kg.

Abacavir Drug Exposures in African Children Under 14 kg Using Pediatric Solid Fixed Dose Combinations According to World Health Organization Weight Bands.

BACKGROUND: The pharmacokinetics of abacavir (ABC) in African children living with HIV (CLHIV) weighing <14 kg and receiving pediatric fixed dose combinations (FDC) according to WHO weight bands dosing are limited. An ABC population pharmacokinetic model was developed to evaluate ABC exposure across different World Health Organization (WHO) weight bands. METHODS: Children enrolled in the LIVING study in Kenya and Uganda receiving ABC/lamivudine (3TC) dispersible tablets (60/30 mg) according to WHO weight bands. A population approach was used to determine the pharmacokinetic parameters. Monte Carlo simulations were conducted using an in silico population with demographic characteristics associated with African CLHIV. ABC exposures (AUC0-24) of 6.4-50.4 mg h/L were used as targets. RESULTS: Plasma samples were obtained from 387 children. A 1-compartment model with allometric scaling of clearance (CL/F) and volume of distribution (V/F) according to body weight best characterized the pharmacokinetic data of ABC. The maturation of ABC CL/F was characterized using a sigmoidal Emax model dependent on postnatal age (50% of adult CL/F reached by 0.48 years of age). Exposures to ABC were within the target range for children weighing 6.0-24.9 kg, but children weighing 3-5.9 kg were predicted to be overexposed. CONCLUSIONS: Lowering the ABC dosage to 30 mg twice daily or 60 mg once daily for children weighing 3-5.9 kg increased the proportion of children within the target and provided comparable exposures. Further clinical study is required to investigate clinical implications and safety of the proposed alternative ABC doses.

Acceptability of decentralizing childhood tuberculosis diagnosis in low-income countries with high tuberculosis incidence: Experiences and perceptions from health care workers in Sub-Saharan Africa and South-East Asia.

Decentralizing childhood tuberculosis services, including diagnosis, is now recommended by the WHO and could contribute to increasing tuberculosis detection in high burden countries. However, implementing microbiological tests and clinical evaluation could be challenging for health care workers (HCWs) in Primary Health Centers (PHCs) and even District Hospitals (DHs). We sought to assess the acceptability of decentralizing a comprehensive childhood tuberculosis diagnosis package from HCWs' perspective. We conducted implementation research nested within the TB-Speed Decentralization study. HCWs from two health districts of Cambodia, Cameroon, Côte d'Ivoire, Mozambique, Sierra Leone, and Uganda implemented systematic screening, nasopharyngeal aspirates (NPA) and stool sample collection with molecular testing, clinical evaluation and chest X-ray (CXR) interpretation. We investigated their experiences and perceptions in delivering the diagnostic package components in 2020-21 using individual semi-structured interviews. We conducted thematic analysis, supported by the Theoretical Framework of Acceptability. HCWs (n = 130, 55% female, median age 36 years, 53% nurses, 72% PHC-based) perceived that systematic screening, although increasing workload, was beneficial as it improved childhood tuberculosis awareness. Most HCWs shared satisfaction and confidence in performing NPA, despite procedure duration, need to involve parents/colleagues and discomfort for children. HCWs shared positive attitudes towards stool sample-collection but were frustrated by delayed stool collection associated with cultural practices, transport and distance challenges. Molecular testing, conducted by nurses or laboratory technicians, was perceived as providing quality results, contributing to diagnosis. Clinical evaluation and diagnosis raised self-efficacy issues and need for continuous training and clinical mentoring. HCWs valued CXR, however complained that technical and logistical problems limited access to digital reports. Referral from PHC to DH was experienced as burdensome. HCWs at DH and PHC-levels perceived and experienced decentralized childhood tuberculosis diagnosis as acceptable. Implementation however could be hampered by feasibility issues, and calls for innovative referral mechanisms for patients, samples and CXR.

Adaption and pilot testing of a lay HIV supporter program for traditional healers: a mixed methods study in rural Uganda.

BACKGROUND: Half of people living with HIV (PLWH) in sub-Saharan Africa default from care within two years. In Uganda, and across sub-Saharan Africa, traditional healers (TH) are ubiquitous and often serve as the first line of health care. We hypothesized that with lay support training, TH could support relinkage to HIV care and ART adherence among rural Ugandan PLWH who have defaulted from HIV care. METHODS: Following the ADAPT-ITT framework, we adapted an evidence-based layperson HIV support program from South Africa for delivery by Ugandan TH. The ADAPT-ITT framework consists of (1) Assessment of needs; (2) Deciding which evidence-based interventions to adapt; (3) Adaptation of interventions; (4) Production of drafted adapted interventions; (5) Topical expert feedback; (6) Integration of expert feedback; (7) Training personnel; and (8) Testing the adapted intervention. The Testing phase was completed via a pilot mixed methods prospective cohort study. The study population included 12 TH practicing in Mbarara Township and 20 adult PLWH with suboptimal ART adherence (CASE adherence index score < 10) who received care from a participating TH and who resided in Mbarara Township. Primary outcome was re-linkage to HIV care within 14 days. Secondary outcomes were ART re-initiation, ART adherence, retention in care after 9 months, and implementation measures. Qualitative interviews were conducted with all participants. RESULTS: Data from the Assessment phase indicated that logistical challenges played an important role in disengagement from care among PLWH who receive care from TH, notably geographical distance to clinics and transportation costs. Additionally, HIV-related stigma and lack of social support were identified as barriers to entering and remaining in HIV care. Two core elements of the intervention were identified during the Production phase: (1) TH facilitating rapid re-linkage to HIV care and (2) TH provision of psychosocial support. In the pilot study phase, baseline median CASE adherence score was 3; only 5% of PLWH were adherent to ART via 4-day recall. The TH-delivered support achieved 100% linkage and ART initiation within 14 days, 95% ART adherence, and 100% of PLWH were retained in HIV care after 9 months. CONCLUSIONS: The ADAPT-ITT framework successfully guided the adaption of a community health worker-delivered intervention for delivery by TH. TH successfully facilitated re-linkage to HIV care, support ART adherence, and retention in care for PLWH when trained as part of a lay support person program. Future studies are needed to evaluate scale-up and long-term impact.

Immunogenicity and safety of fractional doses of 17D-213 yellow fever vaccine in children (YEFE): a randomised, double-blind, non-inferiority substudy of a phase 4 trial.

BACKGROUND: Current supply shortages constrain yellow fever vaccination activities, particularly outbreak response. Although fractional doses of all WHO-prequalified yellow fever vaccines have been shown to be safe and immunogenic in a randomised controlled trial in adults, they have not been evaluated in a randomised controlled trial in young children (9-59 months old). We aimed to assess the immunogenicity and safety of fractional doses compared with standard doses of the WHO-prequalified 17D-213 vaccine in young children. METHODS: This substudy of the YEFE phase 4 study was conducted at the Epicentre Mbarara Research Centre (Mbarara, Uganda). Eligible children were aged 9-59 months without contraindications for vaccination, without history of previous yellow fever vaccination or infection and not requiring yellow fever vaccination for travelling. Participants were randomly assigned, using block randomisation, 1:1 to standard or fractional (one-fifth) dose of yellow fever vaccine. Investigators, participants, and laboratory personnel were blinded to group allocation. Participants were followed for immunogenicity and safety at 10 days, 28 days, and 1 year after vaccination. The primary outcome was non-inferiority in seroconversion (-10 percentage point margin) 28 days after vaccination measured by 50% plaque reduction neutralisation test (PRNT50) in the per-protocol population. Safety and seroconversion at 10 days and 12-16 months after vaccination (given COVID-19 resctrictions) were secondary outcomes. This study is registered with ClinicalTrials.gov, NCT02991495. FINDINGS: Between Feb 20, 2019, and Sept 9, 2019, 433 children were assessed, and 420 were randomly assigned to fractional dose (n=210) and to standard dose (n=210) 17D-213 vaccination. 28 days after vaccination, 202 (97%, 95% CI 95-99) of 207 participants in the fractional dose group and 191 (100%, 98-100) of 191 in the standard dose group seroconverted. The absolute difference in seroconversion between the study groups in the per-protocol population was -2 percentage points (95% CI -5 to 1). 154 (73%) of 210 participants in the fractional dose group and 168 (80%) of 210 in the standard dose group reported at least one adverse event 28 days after vaccination. At 10 days follow-up, seroconversion was lower in the fractional dose group than in the standard dose group. The most common adverse events were upper respiratory tract infections (n=221 [53%]), diarrhoea (n=68 [16%]), rhinorrhoea (n=49 [12%]), and conjunctivitis (n=28 [7%]). No difference was observed in incidence of adverse events and serious adverse events between study groups. CONCLUSIONS: Fractional doses of the 17D-213 vaccine were non-inferior to standard doses in inducing seroconversion 28 days after vaccination in children aged 9-59 months when assessed with PRNT50, but we found fewer children seroconverted at 10 days. The results support consideration of the use of fractional dose of yellow fever vaccines in WHO recommendations for outbreak response in the event of a yellow fever vaccine shortage to include children. FUNDING: Médecins Sans Frontières Foundation.

Acceptability of a new 4-in-1 Abacavir/Lamivudine/Lopinavir/Ritonavir paediatric fixed-dose combination: the caregiver-child dyads' perspective.

Background: Worldwide, 1.7 million children younger than 15 years were living with HIV in 2021. Only 52% of them had access to antiretrovirals (ARVs). Lack of age-appropriate ARV formulations (i.e. easy to swallow for young infants, acceptable taste) remains the main obstacle to the access to ARVs. Therefore, a strawberry-flavoured Abacavir/Lamivudine/Lopinavir/Ritonavir (30/15/40/10 mg) fixed-dose combination of granules in a capsule (4-in-1) for children living with HIV weighing 3-25 kg was developed. Objective: We assessed caregivers' perceived acceptability of the 4-in-1 compared with previous paediatric ARV formulations and factors influencing acceptability. Methods: This exploratory qualitative case study embedded in a phase I/II, open-label, randomized cross-over pharmacokinetic, safety and acceptability study (LOLIPOP) was conducted in three sites in Uganda (May 2019-October 2020). Thirty-six children weighing between 3 and 19.9 kg participated in the main study. We purposively sampled caregiver-child dyads according to weight bands, and conducted 20 semi-structured interviews with caregivers and 5 with healthcare providers. We triangulated these results with a quantitative acceptability questionnaire. We analysed interviews inductively using NVivo12 adopting a thematic analysis approach and acceptability questionnaires descriptively to assess concordance between them. Results: All caregivers found the 4-in-1 formulation highly acceptable and easier to use than previous formulations (i.e. pellets/tables/syrup). Appealing taste, ease of administration, easy storage and children's acceptance contributed to acceptability despite structural challenges of food shortage and HIV stigma. Visible improvements in children's health and comprehensive and tailored healthcare provider support to overcome initial difficulties such as vomiting increased caregivers' acceptance. Concordant results from questionnaire- and interview-data confirmed high acceptability. Conclusion: Caregivers of children in all weight bands in this sample found the 4-in-1 granules highly acceptable compared with the pellets/tablets combination. Healthcare providers' support to caregivers allowed for individual tailoring of drug administration despite challenges such as food shortage. This enabled short-term adherence. These findings informed further practical recommendations. Registration: Clinical trial number: NCT03836833.

Mortality and Cause of Death in Children With Presumptive Disseminated Tuberculosis.

BACKGROUND AND OBJECTIVES: Children experience high tuberculosis (TB)-related mortality but causes of death among those with presumptive TB are poorly documented. We describe the mortality, likely causes of death, and associated risk factors among vulnerable children admitted with presumptive TB in rural Uganda. METHODS: We conducted a prospective study of vulnerable children, defined as <2 years of age, HIV-positive, or severely malnourished, with a clinical suspicion of TB. Children were assessed for TB and followed for 24 weeks. TB classification and likely cause of death were assessed by an expert endpoint review committee, including insight gained from minimally invasive autopsies, when possible. RESULTS: Of the 219 children included, 157 (71.7%) were <2 years of age, 72 (32.9%) were HIV-positive, and 184 (84.0%) were severely malnourished. Seventy-one (32.4%) were classified as "likely tuberculosis" (15 confirmed and 56 unconfirmed), and 72 (32.9%) died. The median time to death was 12 days. The most frequent causes of death, ascertained for 59 children (81.9%), including 23 cases with autopsy results, were severe pneumonia excluding confirmed TB (23.7%), hypovolemic shock due to diarrhea (20.3%), cardiac failure (13.6%), severe sepsis (13.6%), and confirmed TB (10.2%). Mortality risk factors were confirmed TB (adjusted hazard ratio [aHR] = 2.84 [95% confidence interval (CI): 1.19-6.77]), being HIV-positive (aHR = 2.45 [95% CI: 1.37-4.38]), and severe clinical state on admission (aHR = 2.45 [95% CI: 1.29-4.66]). CONCLUSIONS: Vulnerable children hospitalized with presumptive TB experienced high mortality. A better understanding of the likely causes of death in this group is important to guide empirical management.

Stigma of infidelity associated with condom use explains low rates of condom uptake: qualitative data from Uganda and Tanzania.

Despite widespread messaging supporting male (external) condom use to prevent HIV in endemic settings, utilization of condoms is low across sub-Saharan Africa. A thorough understanding of barriers to condom use as a form of HIV prevention is necessary to reduce HIV transmission. Here, we present qualitative data from rural eastern Africa to explain low utilization of condoms among heterosexual adults. Focus groups and interviews were conducted in Tanzania and Uganda between 2016 and 2019. A content analysis approach was used to identify attitudes about condoms and factors related to use/non-use. We found that strategies such as abstinence and being faithful to one's partner are perceived as ideal but rarely achievable methods of HIV prevention. Condoms are used in the setting of "failure" to abstain or be faithful and are therefore stigmatized as markers of infidelity. As such, use within cohabiting and long-term relationships is low. Our data suggest that negative perceptions of condoms may stem from persistent effects of the formerly applied "ABC" HIV prevention approach, a public health messaging strategy that described A-abstinence, B-be faithful, and C-use a condom as tiered prevention tools. Condom uptake could increase if HIV prevention messaging acknowledges existing stigma and reframes condom use for proactive health prevention. These studies were approved by Weill Cornell Medicine (Protocols 1803019105 and 1604017171), Mbarara University of Science and Technology (Protocol 16/0117), Uganda National Council of Science and Technology (Protocol SS-4338), and the Tanzania National Institute for Medical Research (Protocol NIMR/HQ/R.8c/Vol.I/1330).

Condoms are used to prevent HIV infection. Even though public health organizations have encouraged people to use condoms, many people in sub-Saharan Africa do not, especially in sexual encounters with someone that they are living with or married to. In this study, we wanted to understand the reasons that people were not using condoms. Between 2016 and 2019, we spoke with individuals in Uganda in one-on-one interviews about HIV prevention and testing and with focus groups in Tanzania about family planning. We analyzed transcripts of these conversations to find common themes about people's impressions of condom use. We learned that many of our participants believed that abstaining from sex and being faithful were the best ways to prevent HIV infection, but that they were not realistic strategies in the long term. Condoms were thought of as a useful tool for prevention when you "fail" at abstinence and monogamy. They were linked with being unfaithful, so people did not feel comfortable suggesting their use in committed relationships. These findings show that the "ABC" strategy for HIV prevention education may be continuing to make people think negatively about condom use. This strategy presented a tiered approach to HIV prevention, telling people it was best to (A) abstain, (B) be faithful to one's partners, and (C) use a condom. In order to increase engagement with HIV prevention, public health messages need to acknowledge the negative associations between condoms and infidelity.

Effect of systematic tuberculosis detection on mortality in young children with severe pneumonia in countries with high incidence of tuberculosis: a stepped-wedge cluster-randomised trial.

BACKGROUND: Tuberculosis diagnosis might be delayed or missed in children with severe pneumonia because this diagnosis is usually only considered in cases of prolonged symptoms or antibiotic failure. Systematic tuberculosis detection at hospital admission could increase case detection and reduce mortality. METHODS: We did a stepped-wedge cluster-randomised trial in 16 hospitals from six countries (Cambodia, Cameroon, Côte d'Ivoire, Mozambique, Uganda, and Zambia) with high incidence of tuberculosis. Children younger than 5 years with WHO-defined severe pneumonia received either the standard of care (control group) or standard of care plus Xpert MTB/RIF Ultra (Xpert Ultra; Cepheid, Sunnyvale, CA, USA) on nasopharyngeal aspirate and stool samples (intervention group). Clusters (hospitals) were progressively switched from control to intervention at 5-week intervals, using a computer-generated random sequence, stratified on incidence rate of tuberculosis at country level, and masked to teams until 5 weeks before switch. We assessed the effect of the intervention on primary (12-week all-cause mortality) and secondary (including tuberculosis diagnosis) outcomes, using generalised linear mixed models. The primary analysis was by intention to treat. We described outcomes in children with severe acute malnutrition in a post hoc analysis. This study is registered with ClinicalTrials.gov (NCT03831906) and the Pan African Clinical Trial Registry (PACTR202101615120643). FINDINGS: From March 21, 2019, to March 30, 2021, we enrolled 1401 children in the control group and 1169 children in the intervention group. In the intervention group, 1140 (97·5%) children had nasopharyngeal aspirates and 942 (80·6%) had their stool collected; 24 (2·1%) had positive Xpert Ultra. At 12 weeks, 110 (7·9%) children in the control group and 91 (7·8%) children in the intervention group had died (adjusted odds ratio [OR] 0·986, 95% CI 0·597-1·630, p=0·957), and 74 (5·3%) children in the control group and 88 (7·5%) children in the intervention group had tuberculosis diagnosed (adjusted OR 1·238, 95% CI 0·696-2·202, p=0·467). In children with severe acute malnutrition, 57 (23·8%) of 240 children in the control group and 53 (17·8%) of 297 children in the intervention group died, and 36 (15·0%) of 240 children in the control group and 56 (18·9%) of 297 children in the intervention group were diagnosed with tuberculosis. The main adverse events associated with nasopharyngeal aspirates were samples with blood in 312 (27·3%) of 1147 children with nasopharyngeal aspirates attempted, dyspnoea or SpO2 less than 95% in 134 (11·4%) of children, and transient respiratory distress or SpO2 less than 90% in 59 (5·2%) children. There was no serious adverse event related to nasopharyngeal aspirates reported during the trial. INTERPRETATION: Systematic molecular tuberculosis detection at hospital admission did not reduce mortality in children with severe pneumonia. High treatment and microbiological confirmation rates support more systematic use of Xpert Ultra in this group, notably in children with severe acute malnutrition. FUNDING: Unitaid and L'Initiative. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

How informal healthcare providers improve uptake of HIV testing: qualitative results from a randomized controlled trial.

OBJECTIVE: Uganda is HIV-endemic with a prevalence of 5.7%. Lack of epidemic control has been attributed to low engagement with HIV testing. Collaborating with informal healthcare providers, such as traditional healers, has been proposed as a strategy to increase testing uptake. We explored acceptability and implementation of an HIV testing program where traditional healers delivered point-of-care testing and counseling to adults of unknown serostatus (clinicaltrials.gov NCT#03718871). METHODS: This study was conducted in rural, southwestern Uganda. We interviewed participating traditional healers ( N  = 17) and a purposive sample of trial participants ( N  = 107). Healers were practicing within 10 km of Mbarara township, and 18+ years old. Participants were 18+ years old; sexually active; had received care from participating healers; self-reported not receiving an HIV test in prior 12 months; and not previously diagnosed with HIV infection. Interviews explored perceptions of a healer-delivered HIV testing model and were analyzed following a content-analysis approach. RESULTS: Most participants were female individuals ( N  = 68, 55%). Healer-delivered HIV testing overcame structural barriers, such as underlying poverty and rural locations that limited use, as transportation was costly and often prohibitive. Additionally, healers were located in villages and communities, which made services more accessible compared with facility-based testing. Participants also considered healers trustworthy and 'confidential'. These qualities explain some preference for healer-delivered HIV testing, in contrast to 'stigmatizing' biomedical settings. CONCLUSION: Traditional healer-delivered HIV testing was considered more confidential and easily accessible compared with clinic-based testing. Offering services through traditional healers may improve uptake of HIV testing services in rural, medically pluralistic communities.

A Qualitative Exploration of the Referral Process of Children with Common Infections from Private Low-Level Health Facilities in Western Uganda.

Over 50% of sick children are treated by private primary-level facilities, but data on patient referral processes from such facilities are limited. We explored the perspectives of healthcare providers and child caretakers on the referral process of children with common childhood infections from private low-level health facilities in Mbarara District. We carried out 43 in-depth interviews with health workers and caretakers of sick children, purposively selected from 30 facilities, until data saturation was achieved. The issues discussed included the process of referral, challenges in referral completion and ways to improve the process. We used thematic analysis, using a combined deductive/inductive approach. The reasons for where and how to refer were shaped by the patients' clinical characteristics, the caretakers' ability to pay and health workers' perceptions. Caretaker non-adherence to referral and inadequate communication between health facilities were the major challenges to the referral process. Suggestions for improving referrals were hinged on procedures to promote caretaker adherence to referral, including reducing waiting time and minimising the expenses incurred by caretakers. We recommend that triage at referral facilities should be improved and that health workers in low-level private health facilities (LLPHFs) should routinely be included in the capacity-building trainings organised by the Ministry of Health (MoH) and in workshops to disseminate health policies and national healthcare guidelines. Further research should be done on the effect of improving communication between LLPHFs and referral health facilities by affordable means, such as telephone, and the impact of community initiatives, such as transport vouchers, on promoting adherence to referral for sick children.

Capacity to provide care for common childhood infections at low-level private health facilities in Western, Uganda.

BACKGROUND: Low-level private health facilities (LLPHFs) handle a considerable magnitude of sick children in low-resource countries. We assessed capacity of LLPHFs to manage malaria, pneumonia, diarrhea, and, possible severe bacterial infections (PSBIs) in under-five-year-olds. METHODS: We conducted a cross-sectional survey in 110 LLPHFs and 129 health workers in Mbarara District, Uganda between May and December 2019. Structured questionnaires and observation forms were used to collect data on availability of treatment guidelines, vital medicines, diagnostics, and equipment; health worker qualifications; and knowledge of management of common childhood infections. RESULTS: Amoxicillin was available in 97%, parental ampicillin and gentamicin in 77%, zinc tablets and oral rehydration salts in >90% while artemether-lumefantrine was available in 96% of LLPHF. About 66% of facilities stocked loperamide, a drug contraindicated in the management of diarrhoea in children. Malaria rapid diagnostic tests and microscopes were available in 86% of the facilities, timers/clocks in 57% but only 19% of the facilities had weighing scales and 6% stocked oxygen. Only 4% of the LLPHF had integrated management of childhood illness (IMCI) booklets and algorithm charts for management of common childhood illnesses. Of the 129 health workers, 52% were certificate nurses/midwives and (26% diploma nurses/clinical officers; 57% scored averagely for knowledge on management of common childhood illnesses. More than a quarter (38%) of nursing assistants had low knowledge scores. No notable significant differences existed between rural and urban LLPHFs in most parameters assessed. CONCLUSION: Vital first-line medicines for treatment of common childhood illnesses were available in most of the LLPHFs but majority lacked clinical guidelines and very few had oxygen. Majority of health workers had low to average knowledge on management of the common childhood illnesses. There is need for innovative knowledge raising interventions in LLPHFs including refresher trainings, peer support supervision and provision of job aides.

Traditional healer-delivered point-of-care HIV testing versus referral to clinical facilities for adults of unknown serostatus in rural Uganda: a mixed-methods, cluster-randomised trial.

BACKGROUND: HIV counselling and testing are essential to control the HIV epidemic. However, HIV testing uptake is low in sub-Saharan Africa, where many people use informal health-care resources such as traditional healers. We hypothesised that uptake of HIV tests would increase if provided by traditional healers. We aimed to determine the effectiveness of traditional healers delivering HIV testing at point of care compared with referral to local clinics for HIV testing in rural southwestern Uganda. METHODS: We did a mixed-methods study that included a cluster-randomised trial followed by individual qualitative interviews among a sample of participants in Mbarara, Uganda. Traditional healers aged 18 years or older who were located within 8 km of the Mbarara District HIV clinic, were identified in the 2018 population-level census of traditional healers in Mbarara District, and delivered care to at least seven clients per week were randomly assigned (1:1) as clusters to an intervention or a control group. Healers screened their clients for eligibility, and research assistants confirmed eligibility and enrolled clients who were aged 18 years or older, were receiving care from a participating healer, were sexually active (ever had intercourse), self-reported not having received an HIV test in the previous 12 months (and therefore considered to be of unknown serostatus), and had not previously been diagnosed with HIV infection. Intervention group healers provided counselling and offered point-of-care HIV tests to adult clients. Control group healers provided referral for HIV testing at nearby clinics. The primary outcome was the individual receipt of an HIV test within 90 days of study enrolment. Safety and adverse events were recorded and defined on the basis of prespecified criteria. This study is registered with ClinicalTrials.gov, NCT03718871. FINDINGS: Between Aug 2, 2019, and Feb 7, 2020, 17 traditional healers were randomly assigned as clusters (nine to intervention and eight to control), with 500 clients of unknown HIV serostatus enrolled (250 per group). In the intervention group, 250 clients (100%) received an HIV test compared with 57 (23%) in the control group, a 77% (95% CI 73-82) increase in testing uptake, after adjusting for the effect of clustering (p<0·0001). Ten (4%) of 250 clients in the intervention group tested HIV positive, seven of whom self-reported linkage to HIV care. No new HIV cases were identified in the control group. Qualitative interviews revealed that HIV testing delivered by traditional healers was highly acceptable among both providers and clients. No safety or adverse events were reported. INTERPRETATION: Delivery of point-of-care HIV tests by traditional healers to adults of unknown serostatus significantly increased rates of HIV testing in rural Uganda. Given the ubiquity of healers in Africa, this approach holds promise as a new pathway to provide community-based HIV testing, and could have a dramatic effect on uptake of HIV testing in sub-Saharan Africa. FUNDING: US National Institute of Mental Health, National Institutes of Health.

A qualitative study of the perspectives of health workers and policy makers on external support provided to low-level private health facilities in a Ugandan rural district, in management of childhood infections.

BACKGROUND: With the under-five child mortality rate of 46.4 deaths per 1000 live births, Uganda should accelerate measures to reduce child deaths to achieve the Sustainable Development Goal 3. While 60-70% of frontline health services are provided by the private sector, many low-level private health facilities (LLPHF) are unregistered, unregulated, and often miss innovative and quality improvement strategies rolled out by the Ministry of Health. LLPHF need support in order to provide quality health care. OBJECTIVE: To explore the perspectives of health workers and policy makers on external support given to LLPHF providing health care for children in Mbarara District, Uganda. METHODS: We carried out a qualitative study, in which 43 purposively selected health workers and policy makers were interviewed. The issues discussed included their views on the quantity, quality, factors determining support received and preferred modalities of support to LLPHF. We used thematic analysis, employing an inductive approach to code interview transcripts and to identify subthemes and themes. RESULTS: The support currently provided to LLPHF to manage childhood illnesses is inadequate. Health providers emphasised a need for technical capacity building, provision of policies, guidelines and critical supplies as well as adopting a more supportive supervisory approach instead of the current supervision model characterised by policing, fault finding and apportioning blame. Registration of the health facilities and regular submission of reports as well as multi-stakeholder involvement are potential strategies to improve external support. CONCLUSION: The current support received by LLPHF is inadequate in quantity and quality. Capacity building with emphasis on training, provision of critical guidelines and supplies as well as and supportive supervision are key strategies for delivering appropriate external support to LLPHF.

Appropriateness of Care for Common Childhood Infections at Low-Level Private Health Facilities in a Rural District in Western Uganda.

In Uganda, >50% of sick children receive treatment from primary level-private health facilities (HF). We assessed the appropriateness of care for common infections in under-five-year-old children and explored perspectives of healthcare workers (HCW) and policymakers on the quality of healthcare at low-level private health facilities (LLPHF) in western Uganda. This was a mixed-methods parallel convergent study. Employing multistage consecutive sampling, we selected 110 HF and observed HCW conduct 777 consultations of children with pneumonia, malaria, diarrhea or neonatal infections. We purposively selected 30 HCW and 8 policymakers for in-depth interviews. Care was considered appropriate if assessment, diagnosis, and treatment were correct. We used univariable and multivariable logistic regression analyses for quantitative data and deductive thematic analysis for qualitative data. The proportion of appropriate care was 11% for pneumonia, 14% for malaria, 8% for diarrhea, and 0% for neonatal infections. Children with danger signs were more likely to receive appropriate care. Children with diarrhea or ability to feed orally were likely to receive inappropriate care. Qualitative data confirmed care given as often inappropriate, due to failure to follow guidelines. Overall, sick children with common infections were inappropriately managed at LLPHF. Technical support and provision of clinical guidelines should be increased to LLPHF.

Population Pharmacokinetics and Significant Under-Dosing of Anti-Tuberculosis Medications in People with HIV and Critical Illness.

Critical illness from tuberculosis (TB) bloodstream infection results in a high case fatality rate for people living with human immunodeficiency virus (HIV). Critical illness can lead to altered pharmacokinetics and suboptimal drug exposures. We enrolled adults living with HIV and hospitalized with sepsis, with and without meningitis, in Mbarara, Uganda that were starting first-line anti-TB therapy. Serum was collected two weeks after enrollment at 1-, 2-, 4-, and 6-h post-dose and drug concentrations quantified by validated LC-MS/MS methods. Non-compartmental analyses were used to determine total drug exposure, and population pharmacokinetic modeling and simulations were performed to determine optimal dosages. Eighty-one participants were enrolled. Forty-nine completed pharmacokinetic testing: 18 (22%) died prior to testing, 13 (16%) were lost to follow-up and one had incomplete testing. Isoniazid had the lowest serum attainment, with only 4.1% achieving a target exposure over 24 h (AUC0-24) of 52 mg·h/L despite appropriate weight-based dosing. Simulations to reach target AUC0-24 found necessary doses of rifampin of 1800 mg, pyrazinamide of 2500-3000 mg, and for isoniazid 900 mg or higher. Given the high case fatality ratio of TB-related critical illness in this population, an early higher dose anti-TB therapy should be trialed.